1. Field of the Invention
The invention relates to quinazoline and quinoline derivatives, a method of their preparation, and a method of using the same as pharmaceutical agents.
2. Description of the Related Art
Protein tyrosine kinases (PTKs) modulate a wide variety of cellular events, including differentiation, growth, metabolism, and apoptosis. Transmembrane receptor tyrosine kinases (RTKs), members of the PTK family, are the high affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones.
The mechanisms by which most RTKs transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. However, mutations in the transmembrane (TM) domains of RTKs have been implicated in the induction of pathological phenotypes. These mutations are believed to stabilize the RTK dimers, and thus promote unregulated signaling without ligand binding.
Overexpression of PTK in cells can cause weak signals to be amplified. Furthermore, during many steps of cellular signal transfer, the occurrence of mutations or overexpression of PTK can cause false signals. These false signals play a role in carcinogenesis.
Epidermal growth factor receptor (EGFR) is one of the typical examples. EGFR belongs to cell surface receptors of epidermal growth factor receptor tyrosine kinase (EGFR-TK). The receptor family comprises EGF receptor (a protein product of oncogene erbB-1), erbB-2 (c-neu or HER2) receptor, tumor protein mutant erbB-3 receptor, and erbB-4 receptor. EGF and transforming growth factor alpha (TGFα) are the two most important ligands of EGFR. Though the receptor plays a minor role in healthy adults, it is closely related to the pathological process of most cancers, particularly to colon cancer and breast cancer. Therefore, an EGFR-TK inhibitor that can block the transfer of these receptor signals can be used to treat cancers caused by EGFR overexpression, such as colorectal cancer, breast cancer, kidney cancer, lung cancer, and head and neck cancer.
An EGFR-TK inhibitor can also be used to treat other diseases caused by EGFR overexpression, such as psoriasis, nephritis and pancreatitis which are described below.
Conventional treatments for proliferative skin diseases such as psoriasis include anti-cancer drugs, such as methotrexate. However, methotrexate has strong side effects and response is poor within the necessary limited dosage. In psoriatic tissues, TGFα is the main growth factor that is overexpressed. In animal experiments, 50% of transgenic mice with TGFα overexpression produce psoriasis, which suggests that a good inhibitor of EGFR signal transfer mechanism may inhibit psoriasis, i.e., the EGFR-TK inhibitor can relieve psoriasis symptoms.
EGF is an important epithelial mitogen and plays a role in renal tubular cell replication. In streptozotocin-induced diabetic mice, secretion of urine and mRNA of EGF are increased fourfold. Additionally, the expression of EGFR is enhanced in patients with proliferative glomerulonephritis (Roy-Chaudhury et al., Pathology, 1993, 25, 327-332). These findings indicate blocking EGF signal transfer can be used to treat and prevent renal injury. Therefore, it is postulated that an EGFR-TK inhibitor could be used to treat proliferative glomerulonephritis and renal disease induced by diabetes.
It has been reported that in chronic pancreatitis patients the expression of EGFR and TGFα is much higher than in healthy adults (Korc et al., Gut, 1994, 35, 1468). The over expression of erbB-2 receptor has been confirmed in patients with severe chronic pancreatitis (Friess et al., Ann. Surg., 1994, 220, 183). Therefore, it is postulated that an EGFR-TK inhibitor could potentially be used to treat pancreatitis.
During embryonic cell maturation, embryonic cell implantation in endometrium, and other peripheral implantation, EGF and TGFα are present in uterine tissues (Taga, Nippon Sanka Fujinka Gakkai Zasshi, 1992, 44, 939) and EGFR levels are increased (Brown et al., Endocrinology, 1989, 124, 2882). Meanwhile, heparin-binding EGF (HB-EGF) is expressed in the uterus in a blastocyst-mediated process. (Das et al, Development, 1994, 120, 1071). TGFα and EGFR are highly expressed in embryonic cells (Adamson, Mol. Reprod. Dev., 1990, 27, 16). Surgical removal the submandibular gland and treatment with monoclonal antibody against EGFR can greatly reduce the fertility of mice by decreasing the success of embryonic cell implantation (Tsutsumi et al., J. Endocrinology, 1993, 138, 437). These results indicate that an EGFR-TK inhibitor may function as a contraceptive.
WO1992/007844 and WO1992/014716 disclose 2,4-diaminoquinazoline derivatives which are used as potentiators of chemotherapeutic agents in the treatment of cancer.
WO1992/020642 discloses bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
EP520722, EP566226, EP635498, EP602851, WO 1995/019774 and WO 1995/15758 relate to reversible EGF receptor tyrosine kinase inhibitors. These inhibitors belong to the family of aryl and heteroaryl quinazoline derivatives and some exhibit a high inhibitory activity against EGF receptor tyrosine kinase. However, in animal pathological models these inhibitors exhibit low activity. The reason for this lies in that PTK is a catalyst catalyzing a phosphate group to transfer from ATP to a protein tyrosine residue, and the above-mentioned reversible EGF receptor tyrosine kinase inhibitors compete with ATP to bind EGF receptor tyrosine kinase, but in cells the ATP concentration is much higher (mM grade). Thus, the reversible EGF receptor tyrosine kinase inhibitors exhibiting a high activity in vitro have difficulty functioning in pathological animal models. However, since irreversible EGF receptor tyrosine kinase inhibitors do not compete with ATP, they are expected to do better in vivo.
Irreversible EGF receptor tyrosine kinase inhibitors are known and much effort has been devoted to their development. One type of irreversible EGF receptor tyrosine kinase inhibitors features a Michael acceptor at the sixth position of quinazoline, so that a Michael addition reaction can occur between the inhibitor and cysteine sulfhydryl in the active center pocket wall of EGF receptor tyrosine kinase. Furthermore, the activity of the inhibitor has a positive correlation with the activation energy of the Michael addition reaction between the inhibitor and cysteine sulfhydryl.